Anagrelide hydrochloride (AGRYLIN®, XAGRID®) is a novel orally administered imidazoquinazoline which selectively reduces platelet count in humans and is used for such purposes in the treatment of myeloproliferative diseases (MPDs), such as essential thrombocythemia (ET), where an elevated platelet count may put the patient at increased thrombotic risk. The chemical structure of anagrelide, 6,7-dichloro-1,5-dihydroimidazo[2,1-b]-quinazolin-2(3H)-one hydrochloride monohydrate, is shown as the hydrochloride monohydrate in the following formula:

WO 2008/065444 discloses certain 3- and 5-substituted anagrelide derivatives that possess a more advantageous side effect profile. The 3- and 5-substituted anagrelide derivatives possess dramatically lower PDE III inhibitory activity when compared to anagrelide or its active metabolite, yet they still retain potent anti-megakaryocytic activity. The compounds described in WO 2008/065444 are therefore potentially useful and beneficial agents for the treatment of myeloproliferative diseases, such as essential thrombocythemia.
Processes for the preparation of anagrelide are described in U.S. Pat. Nos. 3,932,407; RE31,617; 4,146,718; 4,208,521; 4,357,330; and 5,801,245. Published European patent applications EP 1373268, EP 1700840, EP 1700841, EP 1700842, EP 1700843, and EP 170859 also describe methods for preparing anagrelide.
Commercially, as discussed in U.S. Pat. No. 5,801,245, and as shown in Scheme 1 below, anagrelide has been prepared as the hydrochloride monohydrate (compound IV) from the intermediate, ethyl-N-(6-amino-2,3-dichlorobenzyl)glycine (compound I), either by reaction with cyanogen bromide in hot alcoholic solution, or, preferentially, by reaction with cyanogen bromide in an aprotic solvent such as toluene to give the iminoquinazoline intermediate (compound II), which is isolated and then reacted with a base in a hot solution of alcohol to form anagrelide base (compound III).

The hydrochloride monohydrate anagrelide salt (compound IV) is prepared by adding hydrochloric acid to a methanol slurry of anagrelide base (compound III) and heating to reflux. The hydrochloride salt is then hydrated in a high humidity chamber. These two steps are time-consuming however, and the yield of hydrochloride salt can be poor due to competing acid hydrolysis of the lactam ring and methyl ester formation. After 15 minutes at reflux, the isolated yield is 62% and this decreases to 40% after 2 hours.
Normally, salts are prepared when the free base has undesirable properties such as poor solubility or a non-solid physical state. In this case, both anagrelide base (compound III) and the hydrochloride salt (compound IV) are solids with low aqueous solubility. In addition, the water of crystallization can accelerate decomposition of the parent molecuie through hydrolysis of the lactam ring and this presents long-term stability problems for pharmaceutical anagrelide formulations.
Radiolabeled anagrelide base has been used in pharmacokinetic studies in humans and monkeys and results show complete absorption into blood plasma demonstrating that the base is bioavailable. The free base is converted into the hydrochloride salt in the stomach to enhance absorption. Both the salt and the base exhibit equivalent pharmacological effects, and there is no inherent advantage to using the hydrochloride monohydrate salt as the active pharmaceutical agent.
An important intermediate in these prior art syntheses of anagrelide is ethyl-N-(6-amino-2,3-dichlorobenzyl)glycine (compound I). Ethyl-N-(6-amino-2,3-dichlorobenzyl)glycine (compound I) has been prepared from 2,3-dichloro-6-nitrobenzylamine (compound V) as shown in Scheme 2. This material is no longer readily available commercially, however, as the precursor 2,3-dichloro-nitrobenzonitrile has extreme toxic and skin-irritant properties.

The conventional process for the formation of ethyl-N-(6-amino-2,3-dichlorobenzyl)glycine (compound I) from 1,2,3-trichlorobenzene is shown in U.S. Pat. No. 4,146,718.
An improved process for the formation of ethyl-N-(6-amino-2,3-dichlorobenzyl)glycine (compound I) using the intermediate 2,3-dichloro-6-nitrobenzyl halide (compound VIII), where halide is iodide, chloride or bromide, has been developed as an environmentally acceptable alternative (Scheme 3). The route of preparation from 2,3-dichloro-6-nitro-toluene (compound VII) is described in U.S. Pat. No. 5,801,245, and involves a radical halogenation of the toluene group. Radical conditions can be nonselective, however, and could be difficult to effectively implement in large-scale commercial manufacture.

In both of the reactions shown in Schemes 2 and 3, ethyl-N-(2,3-dichloro-6-nitrobenzyl)glycine (compound VI) is reduced to the 8-amino-2,3-dichlorobenzyl glycine (compound I) by stannous chloride reduction (SnCl2/HCl), A disadvantage of this route is the formation of large amounts of tin-containing waste products. In addition, the strongly acidic reaction conditions can promote chlorination of the aromatic ring, producing a mixture of tri-chloro impurities which are difficult to remove in successive steps.
A further problem with these prior art process is the number of synthetic steps required to produce the quinazoline compounds, with each synthetic step leading both to a reduction in yield and increasing the possibility of competing side reactions. Thus, these conventional synthetic routes require effort to purify the intermediate and final products and may not give an optimal yield. Work up and purification may thus be needed after one or more of the intervening steps and final purification is always required.
WO 2010/070318 describes an improved process for making anagrelide and various analogues thereof. In particular, WO 2010/070318 describes a process for making 3,3-dimethylanagrelide by the process shown in Scheme 4 below.

The process described in WO 2010/070318 possesses a number of advantages over the previously described processes. One particular benefit of the process described in WO 2010/070318 is that the 1,1-dimethyl-ethyl N-(2,3-dichloro-6-nitrobenzyl)glycine intermediate and its 1-unsubstituted or substituted analogues can be formed directly from the corresponding 2,3-dichloro-6-nitrobenzyl alcohol without the need to form an intermediate halo derivative. This leads to a number of processing advantages; particularly on a larger scale. It will be appreciated from Scheme 4 above that WO 2010/070318 describes a three step process to get from the 2,3-dichloro-6-nitrobenzaldehyde intermediate to the 1,1-dimethyl-ethyl N-(2,3-dichloro-6-nitrobenzyl)glycine intermediate.
Despite the improvements offered by the process described in WO 2010/070318, there still remains a need for further improved processes for manufacturing anagrelide or analogues thereof, such as 3,3-dimethylanagrelide, which are efficient and commercially viable to implement on a commercial scale.
It is therefore an object of the present invention to provide an improved synthetic process for the making of anagrelide and its analogues, whether in base or salt form.
It is also an aim of the present invention to provide a synthetically efficient process for the production of anagrelide with a reduced number of synthetic steps and which avoids some or all of the drawbacks associated with the prior art processes. It is also an aim to provide a process in which the convergency (i.e. the bringing together of synthetic fragments) is maximised. It is a further aim to ensure that the need for purification and workup is minimised. It is a particular aim of the present invention to provide a process which minimizes the need for intermediate and final purification steps. It is thus an aim to provide a route to the compounds of formula (I) which offers an improved yield relative to the existing routes. It is a further aim of the process of the present invention to avoid the use of expensive and potentially hazardous reagents and to additionally minimise the complexity and costs associated with the process steps wherever possible.
It is an additional aim of the present invention to make suitable intermediates from readily available starting materials. Ideally this is achieved by an environmentally acceptable method.
Still further objects and advantages of the present invention will become apparent from the details provided in the specification.